PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of agingLink to Publisher's site
 
Aging (Albany NY). 2012 August; 4(8): 567–577.
Published online 2012 August 31.
PMCID: PMC3461344
A filtering strategy identifies FOXQ1 as a potential effector of lamin A dysfunction
Jose Candelario,1,4,5 Leng-Ying Chen,1,4 Paul Marjoram,3 Sita Reddy,2,4 and Lucio Comai1,4
1 Department of Molecular Microbiology & Immunology, University of Southern California, Los Angeles, CA 90033 USA
2 Department of Molecular Biology & Biochemistry, University of Southern California, Los Angeles, CA 90033 USA
3 Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033 USA
4 Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 USA
5 La Jolla Bioengineering Institute, San Diego, CA 9212
Correspondence to:Lucio Comai, PhD; comai/at/usc.edu
Sita Reddy; sitaredd/at/usc.edu
Received July 25, 2012; Accepted August 29, 2012.
Abstract
Small increases in the expression of wild-type prelamin A are sufficient to recapitulate the reduced cell proliferation and altered nuclear membrane morphology observed in cells expressing progerin, the mutant lamin A associated with progeria. We hypothesized that the manifestation of these phenotypes in cells expressing elevated levels of wild-type prelamin A or progerin is caused by the same molecular effectors, which play a central role in the onset of the progeroid phenotype. To experimentally test this hypothesis, we compared the transcriptomes of isogenic diploid fibroblasts expressing progerin or elevated levels of wild-type prelamin A with that of wild-type fibroblasts. We subsequently used the reversion towards normal of two phenotypes, reduced cell growth and dismorphic nuclei, by treatment with farnesyltransferase inhibitor (FTI) or overexpression of ZMPSTE24, as a filtering strategy to identify genes linked to the onset of these two phenotypes. Through this analysis we identified the gene encoding for the transcription factor FOXQ1, as a gene whose expression is induced in both cells expressing progerin and elevated levels of wild-type prelamin A, and subsequently reduced in both cell types upon conditions that ameliorate the phenotypes. We overexpressed FOXQ1 in normal fibroblasts and demonstrated that increased levels of this factor lead to the development of both features that were used in the filtering strategy. These findings suggest a potential link between this transcription factor and cell dysfunction induced by altered prelamin A metabolism.
Keywords: health care, diseases, aging, rapamycin
Articles from Aging (Albany NY) are provided here courtesy of
Impact Journals, LLC